1. Field of the Invention
This invention relates to a therapeutic agent for ovulation disorder caused by Luteinized Unruptured Follicle, and a method for treating ovulation disorder caused by Luteinized Unruptured Follicle.
2. Description of the Related Art
In menstrual cycle, a menstruation and an ovulation are repeated every month for forthcoming pregnancy. This phenomenon is controlled by various hormones such as hypothalamic hormones, pituitary hormones and ovarian hormones, and the mechanism is almost elucidated. However, the local mechanism in ovary that an ovarian follicle grows up to 20 mm in only 14 days and ruptures at 36 hours after Lutenizing Hormone (LH) surge is still obscure.
In 1960, Espey proposed the hypothesis that ovulation is an inflammatory-like reaction.
Based on this hypothesis, the inventor and researchers in his department had studied the relation between ovulation and inflammatory cytokines such as TNF-α, IL-1β, IL-6 for several years. As a result, it was clarified that 1) peripheral serum concentration of Granulocyte Colony-Stimulating Factor (hereinafter referred to as G-CSF) shows a peak at a few days before ovulation, 2) the concentration of the other inflammatory cytokines reveal no significant changes in peripheral serum, 3) G-CSF shows the highest follicular fluid/serum concentration ratio at oocyte pick up in IVF procedure among the tested cytokines, and 4) G-CSF mRNA in the follicular wall increases 10 fold at late luteal phase compared to the other phases in menstrual cycle. Moreover, the inventor and researchers in his department suggested the possibility of G-CSF as a therapeutic agent for ovulation disorders, although it was not clear which kinds of ovulation disorders was G-CSF effective for at that time.
The inventor and researchers in his department published these results in Acta Obst Gynaec Jpn, Vol. 47, No. 5, pp. 493-494 (1995); Newsletter of Tohoku Society of Obstetrics and Gynecology, No. 46, pp. 55-56 (1999); J. Kanazawa Med. Univ., Vol. 24, pp. 42-49 (1999); J. Kanazawa Med. Univ., Vol. 25, pp. 228-233 (1999); Med. J. Noto General Hosp., Vol. 11, pp. 4-11 (2000); JAOG News (supplement), p. 4 (2001); Human Reproduction, Vol. 17, No. 12, pp. 3046-3052 (2002).
It is described in Ali Salmassi, et al., Fertility and Sterility, Vol. 81, Suppl. 1, pp. 786-791 (2004) by the other research group that 1) G-CSF concentration in the follicular fluid is significantly higher than that of serum, and 2) G-CSF and its receptor is located in the luteinized granulose cells. However, these results had been already reported by the inventor and researchers in his department.
In normal menstrual cycle, follicular growth and maturation, ovulation, formation and regression of corpus luteum are repeated periodically. In contrast, there is an ovulation disorder that lutenization without ovulation is observed after follicular growth and maturation. This disorder is called as Luteinized Unruptured Follicle (hereinafter referred to as LUF), and is observed even in normal women. LUF is more commonly observed at the use of some kinds of agents for ovulation induction at the rate of 20% and its recurrence rate is 78.6%. Thus, LUF is an ironical and serious disorder that ovulation induction causes unovulation.